1. Field of the Invention
The present invention relates to new pharmaceutical compositions for the topical administration of hyaluronic acid and its derivatives, as well as other acidic polysaccharides and their derivatives. Such compositions can also contain topical drugs. These compositions are produced by combining gaseous vehicles, excipients, etc., compatible with humans and animals, with active principles, thereby facilitating the homogeneous distribution of the hyaluronic acid, hyaluronic acid derivatives, etc., and topical drugs over the skin for the treatment of burns, ulcerations, sores, wounds, etc.
2. Description of Related Art
Acidic polysaccharides represent an important category of natural polymers commonly used in the preparation of pharmaceutical formulations. Of these, hyaluronic acid, a polysaccharide widely found in animals, comprises alternating units of D-glucuronic acid and N-acetyl-D-glucosamine. It is a linear polymer with a wide range of molecular weights which varies according to the source from which it is extracted and the method of purification. In nature, it is present, for example, in pericellular gels, in the fundamental substance of connective tissues of vertebrates, where it is one of the main components, in the synovial fluid of joints, in the vitreous humor, in human umbilical cord tissue, and in cockscombs.
Specific fractions of hyaluronic acid are known which can be employed in various applications depending upon their molecular weight, as described in European Patent No. 0 138 572. The fraction known as HYALECTIN, having a molecular weight of between 500,000 and 730,000 Daltons, does not possess inflammatory activity, and can therefore be used to substitute endobulbar fluids and in therapy for joint pathologies by intraarticular injection, while the fraction known as HYALASTINE, having a molecular weight of between 50,000 and 100,000 Daltons, is suitable for therapeutic use by virtue of its activity in stimulating tissue repair.
Esters of hyaluronic acid with alcohols wherein the carboxy groups are partially or completely esterified are also known, as is their use in the pharmaceutical and cosmetic fields, and in the area of biodegradable plastic materials (U.S. Pat. Nos. 4,851,521 and 4,965,353). EP 0 341 745 describes inter- and intramolecular esters of hyaluronic acid, wherein all or part of the carboxy groups are esterified with hydroxy groups of the same and/or different molecules of the acidic polysaccharide, and their use in the pharmaceutical and cosmetic fields, and in the area of biodegradable plastic materials.
Hyaluronic acid plays a fundamental role in tissue repair processes, especially in the first stages of the process of the formation of granulation tissue, by stabilizing the coagulation matrix and controlling its degradation, favoring the recruitment of inflammatory cells, such as polymorphonucleocytes and monocytes, of mesenchymal cells, such as fibroblasts and endothelial cells, and directing the subsequent migration of epithelial cells. For a review, see Goa et al., xe2x80x9cHyaluronic Acid: A Review of Its Pharmacology and Use as a Surgical Aid in Ophthalmology, and Its Therapeutic Potential in Joint Disease and Wound Healing,xe2x80x9d Drugs 47(3):536-566, 1994.
It is known that the application of hyaluronic acid solutions hastens the healing of bedsores, wounds, and burns (Wokalek et al. xe2x80x9cTime Course of Wound Healing,xe2x80x9d Journal of Biomaterials Applications 5:337, 1991). The role of hyaluronic acid in the various stages of tissue repair has been described via a theoretical model by Weigel et al., xe2x80x9cA model for the role of hyaluronic acid and fibrin in the early events during the inflammatory response and wound healingxe2x80x9d, J. Theor. Biol. 119:219, 1986.
The foregoing facts demonstrate the importance of hyaluronic acid in the pharmaceutical field.
It is therefore an object of the present invention to provide a pharmaceutical composition, comprising a pharmaceutically effective amount of an acidic polysaccharide and/or a derivative thereof, a gaseous vehicle, and a pharmaceutically acceptable carrier or excipient. Said acidic polysaccharide or derivative thereof can be hyaluronic acid, a pharmaceutically acceptable salt of hyaluronic acid, a partial or total ester of hyaluronic acid with an alcohol, a partial or total intermolecular ester of hyaluronic acid, a partial or total intramolecular ester of hyaluronic acid, a crosslinked ester of hyaluronic acid, an alginic acid ester, an ester of carboxymethylcellulose, an ester of carboxymethylchitin, an ester of carboxymethyl starch, a gellan ester, a crosslinked gellan ester, a pectic acid ester, and a pectinic acid ester. The composition can be in the form of an aerosol or liquid spray, a foam, or a dry spray, and can contain one or more topical drugs.
Another object of the present invention is the use of an acidic polysaccharide or a derivative thereof to produce a pharmaceutical spray composition useful in the treatment of a variety of pathological situations requiring the acceleration of tissue repair, for example in the treatment of burns, sores, ulcerations, and wounds.
Yet another object of the present invention is to provide a therapeutic method, comprising topically administering a pharmaceutical composition comprising a pharmaceutically effective amount of an acidic polysaccharide and/or a derivative thereof in association with a gaseous vehicle and a pharmacologically acceptable excipient. Such composition can optionally contain one or more topical drugs.
Further scope of the applicability of the present invention will become apparent from the detailed description provided below. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments, are merely illustrative, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
The following detailed description of the invention is provided to aid those skilled in the art in practicing the present invention. Even so, the following detailed description should not be construed to unduly limit the present invention, as modifications and variations in the embodiments herein discussed may be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.
The contents of each of the references cited herein are herein incorporated by reference in their entirety.
A number of different acidic polysaccharides can be employed in the present pharmaceutical formulations. Among the preferred acidic polysaccharides are hyaluronic acid and salts thereof of various molecular weights. The production and properties of representative hyaluronic acid fractions HYALECTIN and HYALASTINE and are described in European Patent No. 0 138 572.
Also useful are the partial and total esters of hyaluronic acid with various alcohols, including alkyl and arylalkylic alcohols, as described in U.S. Pat. Nos. 4,851,521 and 4,965,353, and the inter- and intramolecular esters of hyaluronic described in EP 0 341 745, wherein part or all of the carboxyl groups are esterified with hydroxyl groups of the same and/or different molecules of hyaluronic acid. Crosslinked esters of hyaluronic acid, described in EP 0 265 116 are also contemplated for use in the formulations of the present invention.
Other acidic polysaccharides contemplated for use in the present pharmaceutical compositions include alginic acid esters, described in EP 0 251 905; gellan esters, described in EP 0 518 710; crosslinked gellan esters, described in PCT Publication WO 94/03499; esters of pectic acid and pectinic acid, described in PCT Publication WO 93/14129; and esters of carboxymethyl-cellulose, carboxymethylchitin, and carboxymethyl starch, described in EP 0 342 557.
The present invention includes spray compositions employing the foregoing acidic polysaccharides and derivatives, alone or in combination, and further, the inclusion of topical drugs along therewith. Representative topical drugs useful in the present formulations are described in EP 0 197 718, and include antimycotic, antibiotic, antiviral, antimicrobial, anti-inflammatory, and anaesthetic substances routinely used in the art for topical application.
Gaseous vehicles which can be used in the present spray formulations include, for example, n-butane, isobutane, nitrogen, and sterile compressed air.
The dose and distribution of active ingredients delivered via the spray compositions of the present invention are controlled by the valve of the spray atomizer employed, which facilitates delivery of the correct amount of active ingredients over the required area, necessitated by the gravity of the condition to be treated. Such atomizers can deliver single or multiple sprays.
A number of different nonionic and anionic surfactants, such as polyoxyethylene derivatives of sorbitan esters and bi- and trivalent metal soaps, can be employed either alone or in combination in the spray compositions of the present invention. Upon application, these compositions produce a foam, which can be easily rubbed into wounds.
Among the sorbitan ester class of polyoxyethylene derivatives, polyoxyethylene sorbitan monolaurate (TWEEN 20), polyoxyethylene sorbitan monopalmitate (TWEEN 40), polyoxyethylene sorbitan monostearate (TWEEN 60), and polyoxyethylene sorbitan monooleate (TWEEN 80), can be employed in the present spray compositions.
Among the bi- and trivalent metal soaps, aluminum stearate and zinc stearate can be employed.
For purely illustrative purposes, described below are some examples of formulations according to the present invention.